Old age increases microglial senescence, exacerbates secondary neuroinflammation, and worsens neurological outcomes after acute traumatic brain injury in mice
Old age increases microglial senescence, exacerbates secondary neuroinflammation, and worsens neurological outcomes after acute traumatic brain injury in mice
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DOI：
10.1016/j.neurobiolaging.2019.02.010
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发表时间：
2019-05-01
影响因子：
4.2
通讯作者：
Loane, David J.
中科院分区：
文献类型：
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作者：
Ritzel, Rodney M.;Doran, Sarah J.;Loane, David J.
创伤性脑损伤（TBI）后，与年轻人相比，65岁以上的人显示出更高的死亡率和更差的功能结果。由于神经炎症是TBI后继发性损伤的关键病理生物学机制，我们研究了衰老如何影响创伤后小胶质细胞反应和功能结局。对年轻（3月龄）和老年（18月龄）雄性C57 BL/6小鼠进行中等水平的受控皮质撞击或假手术，并评价神经功能。在损伤后72小时，使用流式细胞术离体评估脑、血液和脾白细胞计数。老年小鼠在前肢握力、平衡和运动协调、自发运动活动和焦虑样行为方面表现出更严重的缺陷。这些动物还表现出更稳健的小胶质细胞增殖和显著更高数量的脑浸润白细胞。老年小鼠中的小胶质细胞表现出吞噬活性受损和白细胞介素-1 β（IL-1 β）产生增加。老年TBI小鼠的浸润骨髓细胞也有吞噬功能缺陷，但表现出减少的促炎细胞因子产生和更大的活性氧产生。在小胶质细胞和受损皮质中，几种衰老标志物（Bcl-2、p16（ink 4a）、p21（cip 1a）、脂褐素和H2 AX [pS139]）的表达随着年龄和/或TBI而增加。尽管循环血液中性粒细胞的数量随年龄的变化没有差异，但年轻小鼠表现出更明显的TBI诱导的脾肿大和脾髓样细胞扩增。因此，老年动物中更差的创伤后行为结果与夸大的小胶质细胞反应、增加的白细胞侵袭和衰老标记物的上调相关。(C)2019爱思唯尔公司All rights reserved.
After traumatic brain injury (TBI), individuals aged over 65 years show increased mortality and worse functional outcomes compared with younger persons. As neuroinflammation is a key pathobiological mechanism of secondary injury after TBI, we examined how aging affects post-traumatic microglial responses and functional outcomes. Young (3-month-old) and aged (18-month-old) male C57BL/6 mice were subjected to moderate-level controlled cortical impact or sham surgery, and neurological function was evaluated. At 72 hours after injury, brain, blood, and spleen leukocyte counts were assessed ex vivo using flow cytometry. Aged mice demonstrated more severe deficits in forelimb grip strength, balance and motor coordination, spontaneous locomotor activity, and anxiety-like behavior. These animals also exhibited more robust microglial proliferation and significantly higher numbers of brain-infiltrating leukocytes. Microglia in aged mice showed impairments in phagocytic activity and higher production of interleukin-1 beta (IL-1 beta). Infiltrating myeloid cells in aged TBI mice also had deficits in phagocytosis but showed diminished proinflammatory cytokine production and greater reactive oxygen species production. Expression of several senescence markers (Bcl-2, p16(ink4a), p21(cip1a), lipofuscin, and H2AX [pS139]) was increased with age and/or TBI in both microglia and injured cortex. Although there was no difference in the number of circulating blood neutrophils as a function of age, young mice exhibited more pronounced TBI-induced splenomegaly and splenic myeloid cell expansion. Thus, worse post-traumatic behavioral outcomes in aged animals are associated with exaggerated microglial responses, increased leukocyte invasion, and upregulation of senescence markers. (C) 2019 Elsevier Inc. All rights reserved.